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Artikel: Editorial: The Bone Marrow Niche in Normal and Malignant Haematopoiesis.

Colombo, Michela / Norfo, Ruggiero / Bianchi, Giada / Roccaro, Aldo M

Frontiers in cell and developmental biology

2022 Band 10, Seite(n) 870114

Sprache	Englisch
Erscheinungsdatum	2022-02-28
Erscheinungsland	Switzerland
Dokumenttyp	Editorial
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.870114
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Ancient genomic linkage couples metabolism with erythroid development.

Preston, Alexandra E / Frost, Joe N / Badat, Mohsin / Teh, Megan / Armitage, Andrew E / Norfo, Ruggiero / Wideman, Sarah K / Hanifi, Muhammad / White, Natasha / Roy, Noémi / Ghesquiere, Bart / Babbs, Christian / Kassouf, Mira / Davies, James / Hughes, Jim R / Beagrie, Rob / Higgs, Douglas R / Drakesmith, Hal

bioRxiv : the preprint server for biology

2023

Abstract: Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce ... ...

Abstract	Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes
Sprache	Englisch
Erscheinungsdatum	2023-09-25
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.09.25.558944
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells.

Matsuoka, Sahoko / Facchini, Raffaella / Luis, Tiago C / Carrelha, Joana / Woll, Petter S / Mizukami, Takuo / Wu, Bishan / Boukarabila, Hanane / Buono, Mario / Norfo, Ruggiero / Arai, Fumio / Suda, Toshio / Mead, Adam J / Nerlov, Claus / Jacobsen, Sten Eirik W

Blood

2023 Band 142, Heft 19, Seite(n) 1622–1632

Abstract: A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble ... ...

Abstract	A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.
Mesh-Begriff(e)	Mice ; Animals ; Stem Cell Factor/metabolism ; Endothelial Cells ; Hematopoietic Stem Cells/metabolism ; Bone Marrow/metabolism ; Bone and Bones ; Stem Cell Niche ; Bone Marrow Cells/metabolism
Chemische Substanzen	Stem Cell Factor
Sprache	Englisch
Erscheinungsdatum	2023-08-07
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022019018
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Genomic landscape of megakaryopoiesis and platelet function defects.

Bianchi, Elisa / Norfo, Ruggiero / Pennucci, Valentina / Zini, Roberta / Manfredini, Rossella

Blood

2016 Band 127, Heft 10, Seite(n) 1249–1259

Abstract: Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of lineage commitment decisions that ultimately lead to the production of polyploid ... ...

Abstract	Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of lineage commitment decisions that ultimately lead to the production of polyploid megakaryocytes. On average, megakaryocytes release 10(11) platelets per day into the blood that repair vascular injuries and prevent excessive bleeding. This differentiation process is tightly controlled by exogenous and endogenous factors, which have been the topics of intense research in the hematopoietic field. Indeed, a skewing of megakaryocyte commitment and differentiation may entail the onset of myeloproliferative neoplasms and other preleukemic disorders together with acute megakaryoblastic leukemia, whereas quantitative or qualitative defects in platelet production can lead to inherited platelet disorders. The recent advent of next-generation sequencing has prompted mapping of the genomic landscape of these conditions to provide an accurate view of the underlying lesions. The aims of this review are to introduce the physiological pathways of megakaryopoiesis and to present landmark studies on acquired and inherited disorders that target them. These studies have not only introduced a new era in the fields of molecular medicine and targeted therapies but may also provide us with a better understanding of the mechanisms underlying normal megakaryopoiesis and thrombopoiesis that can inform efforts to create alternative sources of megakaryocytes and platelets.
Mesh-Begriff(e)	Animals ; Blood Platelet Disorders/genetics ; Blood Platelet Disorders/metabolism ; Blood Platelet Disorders/pathology ; Blood Platelets/metabolism ; Blood Platelets/pathology ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Genetic Diseases, Inborn/pathology ; Genome, Human ; High-Throughput Nucleotide Sequencing ; Humans ; Megakaryocytes/metabolism ; Megakaryocytes/pathology ; Thrombopoiesis/genetics
Sprache	Englisch
Erscheinungsdatum	2016-01-19
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-07-607952
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner.

Nature communications

2023 Band 14, Heft 1, Seite(n) 6062

Abstract: Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by ...

Abstract	Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr
Mesh-Begriff(e)	Humans ; Interleukin-1/metabolism ; Hematopoietic Stem Cells/metabolism ; Bone Marrow/metabolism ; Megakaryocytes ; Thrombocytopenia/metabolism
Chemische Substanzen	Interleukin-1
Sprache	Englisch
Erscheinungsdatum	2023-09-28
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41691-y
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells.

Carrelha, Joana / Mazzi, Stefania / Winroth, Axel / Hagemann-Jensen, Michael / Ziegenhain, Christoph / Högstrand, Kari / Seki, Masafumi / Brennan, Margs S / Lehander, Madeleine / Wu, Bishan / Meng, Yiran / Markljung, Ellen / Norfo, Ruggiero / Ishida, Hisashi / Belander Strålin, Karin / Grasso, Francesca / Simoglou Karali, Christina / Aliouat, Affaf / Hillen, Amy /

Chari, Edwin / Siletti, Kimberly / Thongjuea, Supat / Mead, Adam J / Linnarsson, Sten / Nerlov, Claus / Sandberg, Rickard / Yoshizato, Tetsuichi / Woll, Petter S / Jacobsen, Sten Eirik W

Nature immunology

2024 Band 25, Heft 6, Seite(n) 1007–1019

Abstract: Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for ...

Abstract	Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.
Mesh-Begriff(e)	Blood Platelets/immunology ; Blood Platelets/metabolism ; Animals ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Mice ; Cell Differentiation/immunology ; Megakaryocytes/cytology ; Cell Lineage ; Mice, Inbred C57BL ; Hematopoiesis ; Thrombopoiesis ; Mice, Knockout ; Humans ; Multipotent Stem Cells/cytology ; Multipotent Stem Cells/metabolism ; Multipotent Stem Cells/immunology
Sprache	Englisch
Erscheinungsdatum	2024-05-30
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-024-01845-6
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Rapid Emergence of Chronic Lymphocytic Leukemia During JAK2 Inhibitor Therapy in a Patient With Myelofibrosis.

Sousos, Nikolaos / Buck, Gemma / Rodriguez-Meira, Alba / Norfo, Ruggiero / Hamblin, Angela / Pezzella, Francesco / Davies, Jennifer / Hublitz, Philip / Psaila, Bethan / Mead, Adam J

HemaSphere

2020 Band 4, Heft 3, Seite(n) e356

Sprache	Englisch
Erscheinungsdatum	2020-05-27
Erscheinungsland	United States
Dokumenttyp	Letter
ISSN	2572-9241
ISSN (online)	2572-9241
DOI	10.1097/HS9.0000000000000356
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution.

Rodriguez-Meira, Alba / Norfo, Ruggiero / Wen, Sean / Chédeville, Agathe L / Rahman, Haseeb / O'Sullivan, Jennifer / Wang, Guanlin / Louka, Eleni / Kretzschmar, Warren W / Paterson, Aimee / Brierley, Charlotte / Martin, Jean-Edouard / Demeule, Caroline / Bashton, Matthew / Sousos, Nikolaos / Moralli, Daniela / Subha Meem, Lamia / Carrelha, Joana / Wu, Bishan /

Hamblin, Angela / Guermouche, Helene / Pasquier, Florence / Marzac, Christophe / Girodon, François / Vainchenker, William / Drummond, Mark / Harrison, Claire / Chapman, J Ross / Plo, Isabelle / Jacobsen, Sten Eirik W / Psaila, Bethan / Thongjuea, Supat / Antony-Debré, Iléana / Mead, Adam J

Nature genetics

2023 Band 55, Heft 9, Seite(n) 1531–1541

Abstract: Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution ... ...

Abstract	Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.
Mesh-Begriff(e)	Humans ; Multiomics ; Neoplasm Proteins ; Inflammation/genetics ; Alleles ; Leukemia/genetics ; Tumor Suppressor Protein p53/genetics
Chemische Substanzen	Neoplasm Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53
Sprache	Englisch
Erscheinungsdatum	2023-09-04
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-023-01480-1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: miR-382-5p Controls Hematopoietic Stem Cell Differentiation Through the Downregulation of MXD1.

Zini, Roberta / Rossi, Chiara / Norfo, Ruggiero / Pennucci, Valentina / Barbieri, Greta / Ruberti, Samantha / Rontauroli, Sebastiano / Salati, Simona / Bianchi, Elisa / Manfredini, Rossella

Stem cells and development

2016 Band 25, Heft 19, Seite(n) 1433–1443

Abstract: microRNAs are key regulators of gene expression that control stem cell fate by posttranscriptional downregulation of hundreds of target genes through seed pairing in their 3' untranslated region. In fact, miRNAs tightly regulate fundamental stem cell ... ...

Abstract	microRNAs are key regulators of gene expression that control stem cell fate by posttranscriptional downregulation of hundreds of target genes through seed pairing in their 3' untranslated region. In fact, miRNAs tightly regulate fundamental stem cell processes, like self-renewal, proliferation, and differentiation; therefore, miRNA deregulation may contribute to the development of solid tumors and hematological malignancies. miR-382-5p has been found to be upregulated in patients with myeloid neoplasms, but its role in normal hematopoiesis is still unknown. In this study, we demonstrated that miR-382-5p overexpression in CD34(+) hematopoietic stem/progenitor cells (HSPCs) leads to a significant decrease of megakaryocyte precursors coupled to increase of granulocyte ones. Furthermore, by means of a computational analysis using different prediction algorithms, we identified several putative mRNA targets of miR-382-5p that are downregulated upon miRNA overexpression (ie, FLI1, GATA2, MAF, MXD1, RUNX1, and SGK1). Among these, we validated MXD1 as real target of miR-382-5p by luciferase reporter assay. Finally, we showed that MXD1 knockdown mimics the effects of miR-382-5p overexpression on granulocyte and megakaryocyte differentiation of CD34(+) cells. Overall, our results demonstrated that miR-382-5p expression favors the expansion of granulocyte lineage and impairs megakaryocyte commitment through MXD1 downregulation. Therefore, our data showed for the first time that the miR-382-5p/MXD1 axis plays a critical role in myelopoiesis by affecting the lineage choice of CD34(+) HSPCs.
Mesh-Begriff(e)	Antigens, CD34/metabolism ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Lineage/drug effects ; Cell Lineage/genetics ; Cells, Cultured ; Clone Cells ; Collagen/pharmacology ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Gene Silencing/drug effects ; Genes, Reporter ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Luciferases/metabolism ; Methylcellulose/pharmacology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Reproducibility of Results
Chemische Substanzen	Antigens, CD34 ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; MIRN382 microRNA, human ; MXD1 protein, human ; MicroRNAs ; Repressor Proteins ; Methylcellulose (9004-67-5) ; Collagen (9007-34-5) ; Luciferases (EC 1.13.12.-)
Sprache	Englisch
Erscheinungsdatum	2016-10-01
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2142214-X
ISSN	1557-8534 ; 1547-3287
ISSN (online)	1557-8534
ISSN	1547-3287
DOI	10.1089/scd.2016.0150
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia.

The Journal of experimental medicine

2021 Band 218, Heft 2

Abstract: Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA ...

Abstract	Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.
Mesh-Begriff(e)	Animals ; Biomarkers, Tumor/genetics ; Cell Line ; Female ; Hematopoietic Stem Cells/pathology ; Humans ; Leukemia, Myelomonocytic, Juvenile/genetics ; Leukemia, Myelomonocytic, Juvenile/pathology ; Male ; Mice ; Mutation/genetics ; Neoplastic Stem Cells/pathology ; Signal Transduction/genetics ; Up-Regulation/genetics
Chemische Substanzen	Biomarkers, Tumor
Sprache	Englisch
Erscheinungsdatum	2021-01-08
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20180853
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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